tbuckley/cabot-search huggingface dataset:
Analysis of transcriptomic features reveals molecular endotypes of SLE with clinical implications
Authors: Erika L. Hubbard, Prathyusha Bachali, Kathryn M. Kingsmore, Yisha He, Michelle D. Catalina, Amrie C. Grammer, Peter E. Lipsky
Journal: Genome Medicine (2023)

Abstract Background Systemic lupus erythematosus (SLE) is known to be clinically heterogeneous. Previous efforts to characterize subsets of SLE patients based on gene expression analysis have not been reproduced because of small sample sizes or technical problems. The aim of this study was to develop a robust patient stratification system using gene expression profiling to characterize individual lupus patients. Methods We employed gene set variation analysis (GSVA) of informative gene modules to identify molecular endotypes of SLE patients, machine learning (ML) to classify individual patients into molecular subsets, and logistic regression to develop a composite metric estimating the scope of immunologic perturbations. SHapley Additive ExPlanations (SHAP) revealed the impact of specific features on patient sub-setting. Results Using five datasets comprising 2183 patients, eight SLE endotypes were identified. Expanded analysis of 3166 samples in 17 datasets revealed that each endotype had unique gene enrichment patterns, but not all endotypes were observed in all datasets. ML algorithms trained on 2183 patients and tested on 983 patients not used to develop the model demonstrated effective classification into one of eight endotypes. SHAP indicated a unique array of features influential in sorting individual samples into each of the endotypes. A composite molecular score was calculated for each patient and significantly correlated with standard laboratory measures. Significant differences in clinical characteristics were associated with different endotypes, with those with the least perturbed transcriptional profile manifesting lower disease severity. The more abnormal endotypes were significantly more likely to experience a severe flare over the subsequent 52 weeks while on standard-of-care medication and specific endotypes were more likely to be clinical responders to the investigational product tested in one clinical trial analyzed (tabalumab). Conclusions Transcriptomic profiling and ML reproducibly separated lupus patients into molecular endotypes with significant differences in clinical features, outcomes, and responsiveness to therapy. Our classification approach using a composite scoring system based on underlying molecular abnormalities has both staging and prognostic relevance.
The evolution and mutational robustness of chromatin accessibility in Drosophila
Authors: Samuel Khodursky, Eric B. Zheng, Nicolas Svetec, Sylvia M. Durkin, Sigi Benjamin, Alice Gadau, Xia Wu, Li Zhao
Journal: Genome biology (2023)

Abstract Background The evolution of genomic regulatory regions plays a critical role in shaping the diversity of life. While this process is primarily sequence-dependent, the enormous complexity of biological systems complicates the understanding of the factors underlying regulation and its evolution. Here, we apply deep neural networks as a tool to investigate the sequence determinants underlying chromatin accessibility in different species and tissues of Drosophila . Results We train hybrid convolution-attention neural networks to accurately predict ATAC-seq peaks using only local DNA sequences as input. We show that our models generalize well across substantially evolutionarily diverged species of insects, implying that the sequence determinants of accessibility are highly conserved. Using our model to examine species-specific gains in accessibility, we find evidence suggesting that these regions may be ancestrally poised for evolution. Using in silico mutagenesis, we show that accessibility can be accurately predicted from short subsequences in each example. However, in silico knock-out of these sequences does not qualitatively impair classification, implying that accessibility is mutationally robust. Subsequently, we show that accessibility is predicted to be robust to large-scale random mutation even in the absence of selection. Conversely, simulations under strong selection demonstrate that accessibility can be extremely malleable despite its robustness. Finally, we identify motifs predictive of accessibility, recovering both novel and previously known motifs. Conclusions These results demonstrate the conservation of the sequence determinants of accessibility and the general robustness of chromatin accessibility, as well as the power of deep neural networks to explore fundamental questions in regulatory genomics and evolution.
Recurrent DNMT3B rearrangements are associated with unfavorable outcome in dicentric (9;20)-positive pediatric BCP-ALL
Authors: Željko Antić, Alena van Bömmel, Konstantin Riege, Jana Lentes, Charlotte Schröder, Julia Alten, Cornelia Eckert, Lara Fuhrmann, Doris Steinemann, Lennart Lenk, Denis M. Schewe, Martin Zimmermann, Martin Schrappe, Brigitte Schlegelberger, Gunnar Cario, Steve Hoffmann, Anke K. Bergmann
Journal: Leukemia (2023)
Decolonisation: London’s famous school of “tropical medicine” and its uncomfortable identity
Authors: Mun-Keat Looi
Journal: BMJ (2023)

One of Britain’s most renowned medical institutions is grappling with its colonial history and the effects of racism and inequality on its culture today. In the first of a two part series <b>Mun-Keat Looi</b> asks whether its efforts on decolonisation are enough
Author Correction: Tau-targeting antisense oligonucleotide MAPTRx in mild Alzheimer’s disease: a phase 1b, randomized, placebo-controlled trial
Authors: Catherine J. Mummery, Anne Börjesson-Hanson, Daniel J. Blackburn, Everard G. B. Vijverberg, Peter Paul De Deyn, Simon Ducharme, Michael Jonsson, Anja Schneider, Juha O. Rinne, Albert C. Ludolph, Ralf Bodenschatz, Holly Kordasiewicz, Eric E. Swayze, Bethany Fitzsimmons, Laurence Mignon, Katrina M. Moore, Chris Yun, Tiffany Baumann, Dan Li, Daniel A. Norris, Rebecca Crean, Danielle L. Graham, Ellen Huang, Elena Ratti, C. Frank Bennett, Candice Junge, Roger M. Lane
Journal: Nature Medicine (2023)
Navigating and diagnosing cognitive frailty in research and clinical domains
Authors: Monica M. Nader, Caglar Cosarderelioglu, Emily Miao, Heather Whitson, Qian-Li Xue, Francine Grodstein, Esther Oh, Luigi Ferrucci, David A. Bennett, Jeremy D. Walston, Claudene George, Peter M. Abadir
Journal: Nature Aging (2023)
Author Correction: Hypothalamic GABRA5-positive neurons control obesity via astrocytic GABA
Authors: Moonsun Sa, Eun-Seon Yoo, Wuhyun Koh, Mingu Gordon Park, Hyun-Jun Jang, Yong Ryoul Yang, Mridula Bhalla, Jae-Hun Lee, Jiwoon Lim, Woojin Won, Jea Kwon, Joon-Ho Kwon, Yejin Seong, Byungeun Kim, Heeyoung An, Seung Eun Lee, Ki Duk Park, Pann-Ghill Suh, Jong-Woo Sohn, C. Justin Lee
Journal: Nature Metabolism (2023)
Regulatory controls of duplicated gene expression during fiber development in allotetraploid cotton
Authors: Jiaqi You, Zhenping Liu, Zhengyang Qi, Yizan Ma, Mengling Sun, Ling Su, Hao Niu, Yabing Peng, Xuanxuan Luo, Mengmeng Zhu, Yuefan Huang, Xing Chang, Xiubao Hu, Yuqi Zhang, Ruizhen Pi, Yuqi Liu, Qingying Meng, Jianying Li, Qinghua Zhang, Longfu Zhu, Zhongxu Lin, Ling Min, Daojun Yuan, Corrinne E. Grover, David D. Fang, Keith Lindsey, Jonathan F. Wendel, Lili Tu, Xianlong Zhang, Maojun Wang
Journal: Nature Genetics (2023)

Polyploidy complicates transcriptional regulation and increases phenotypic diversity in organisms. The dynamics of genetic regulation of gene expression between coresident subgenomes in polyploids remains to be understood. Here we document the genetic regulation of fiber development in allotetraploid cotton Gossypium hirsutum by sequencing 376 genomes and 2,215 time-series transcriptomes. We characterize 1,258 genes comprising 36 genetic modules that control staged fiber development and uncover genetic components governing their partitioned expression relative to subgenomic duplicated genes (homoeologs). Only about 30% of fiber quality-related homoeologs show phenotypically favorable allele aggregation in cultivars, highlighting the potential for subgenome additivity in fiber improvement. We envision a genome-enabled breeding strategy, with particular attention to 48 favorable alleles related to fiber phenotypes that have been subjected to purifying selection during domestication. Our work delineates the dynamics of gene regulation during fiber development and highlights the potential of subgenomic coordination underpinning phenotypes in polyploid plants.
Genome-wide association meta-analysis identifies risk loci for abdominal aortic aneurysm and highlights PCSK9 as a therapeutic target
Authors: Tanmoy Roychowdhury, Derek Klarin, Michael G. Levin, Joshua M. Spin, Yae Hyun Rhee, Alicia Deng, Colwyn A. Headley, Noah L. Tsao, Corry Gellatly, Verena Zuber, Fred Shen, Whitney E. Hornsby, Ina Holst Laursen, Shefali S. Verma, Adam E. Locke, Gudmundur Einarsson, Gudmar Thorleifsson, Sarah E. Graham, Ozan Dikilitas, Jack W. Pattee, Renae L. Judy, Ferran Pauls-Verges, Jonas B. Nielsen, Brooke N. Wolford, Ben M. Brumpton, Jaume Dilmé, Olga Peypoch, Laura Calsina Juscafresa, Todd L. Edwards, Dadong Li, Karina Banasik, Søren Brunak, Rikke L. Jacobsen, Minerva T. Garcia-Barrio, Jifeng Zhang, Lars M. Rasmussen, Regent Lee, Ashok Handa, Anders Wanhainen, Kevin Mani, Jes S. Lindholt, Lasse M. Obel, Ewa Strauss, Grzegorz Oszkinis, Christopher P. Nelson, Katie L. Saxby, Joost A. van Herwaarden, Sander W. van der Laan, Jessica van Setten, Mercedes Camacho, Frank M. Davis, Rachael Wasikowski, Lam C. Tsoi, Johann E. Gudjonsson, Jonathan L. Eliason, Dawn M. Coleman, Peter K. Henke, Santhi K. Ganesh, Y. Eugene Chen, Weihua Guan, James S. Pankow, Nathan Pankratz, Ole B. Pedersen, Christian Erikstrup, Weihong Tang, Kristian Hveem, Daniel Gudbjartsson, Solveig Gretarsdottir, Unnur Thorsteinsdottir, Hilma Holm, Kari Stefansson, Manuel A. Ferreira, Aris Baras, Iftikhar J. Kullo, Marylyn D. Ritchie, Alex H. Christensen, Kasper K. Iversen, Nikolaj Eldrup, Henrik Sillesen, Sisse R. Ostrowski, Henning Bundgaard, Henrik Ullum, Stephen Burgess, Dipender Gill, Katherine Gallagher, Maria Sabater-Lleal, Frank Dudbridge, Nilesh J. Samani, Ida Surakka, Gregory T. Jones, Matthew J. Bown, Philip S. Tsao, Cristen J. Willer, Scott M. Damrauer
Journal: Nature Genetics (2023)

Abdominal aortic aneurysm (AAA) is a common disease with substantial heritability. In this study, we performed a genome-wide association meta-analysis from 14 discovery cohorts and uncovered 141 independent associations, including 97 previously unreported loci. A polygenic risk score derived from meta-analysis explained AAA risk beyond clinical risk factors. Genes at AAA risk loci indicate involvement of lipid metabolism, vascular development and remodeling, extracellular matrix dysregulation and inflammation as key mechanisms in AAA pathogenesis. These genes also indicate overlap between the development of AAA and other monogenic aortopathies, particularly via transforming growth factor β signaling. Motivated by the strong evidence for the role of lipid metabolism in AAA, we used Mendelian randomization to establish the central role of nonhigh-density lipoprotein cholesterol in AAA and identified the opportunity for repurposing of proprotein convertase, subtilisin/kexin-type 9 (PCSK9) inhibitors. This was supported by a study demonstrating that PCSK9 loss of function prevented the development of AAA in a preclinical mouse model.
Prenatal vitamin D supplementation to prevent childhood asthma: 15-year results from the Vitamin D Antenatal Asthma Reduction Trial (VDAART)
Authors: Scott T. Weiss, Hooman Mirzakhani, Vincent J. Carey, George T. O’Connor, Robert S. Zeiger, Leonard B. Bacharier, Jeffrey Stokes, Augusto A. Litonjua
Journal: Journal of Allergy and Clinical Immunology (2023)
Three-dimensional genome architecture coordinates key regulators of lineage specification in mammary epithelial cells
Authors: Michael J.G. Milevskiy, Hannah D. Coughlan, Serena R. Kane, Timothy M. Johanson, Somayeh Kordafshari, Wing Fuk Chan, Minhsuang Tsai, Elliot Surgenor, Stephen Wilcox, Rhys S. Allan, Yunshun Chen, Geoffrey J. Lindeman, Gordon K. Smyth, Jane E. Visvader
Journal: Cell Genomics (2023)

Although lineage-specific genes have been identified in the mammary gland, little is known about the contribution of the 3D genome organization to gene regulation in the epithelium. Here, we describe the chromatin landscape of the three major epithelial subsets through integration of long- and short-range chromatin interactions, accessibility, histone modifications, and gene expression. While basal genes display exquisite lineage specificity via distal enhancers, luminal-specific genes show widespread promoter priming in basal cells. Cell specificity in luminal progenitors is largely mediated through extensive chromatin interactions with super-enhancers in gene-body regions in addition to interactions with polycomb silencer elements. Moreover, lineage-specific transcription factors appear to be controlled through cell-specific chromatin interactivity. Finally, chromatin accessibility rather than interactivity emerged as a defining feature of the activation of quiescent basal stem cells. This work provides a comprehensive resource for understanding the role of higher-order chromatin interactions in cell-fate specification and differentiation in the adult mouse mammary gland.
Mycobacterium tuberculosis suppresses host DNA repair to boost its intracellular survival
Authors: Shanshan Liu, Liru Guan, Cheng Peng, Yuanna Cheng, Hongyu Cheng, Fei Wang, Mingtong Ma, Ruijuan Zheng, Zhe Ji, Pengfei Cui, Yefei Ren, Liru Li, Chenyue Shi, Jie Wang, Xiaochen Huang, Xia Cai, Di Qu, Haiping Zhang, Zhiyong Mao, Haipeng Liu, Peng Wang, Wei Sha, Hua Yang, Lin Wang, Baoxue Ge
Journal: Cell Host & Microbe (2023)

Mycobacterium tuberculosis (Mtb) triggers distinct changes in macrophages, resulting in the formation of lipid droplets that serve as a nutrient source. We discover that Mtb promotes lipid droplets by inhibiting DNA repair responses, resulting in the activation of the type-I IFN pathway and scavenger receptor-A1 (SR-A1)-mediated lipid droplet formation. Bacterial urease C (UreC, Rv1850) inhibits host DNA repair by interacting with RuvB-like protein 2 (RUVBL2) and impeding the formation of the RUVBL1-RUVBL2-RAD51 DNA repair complex. The suppression of this repair pathway increases the abundance of micronuclei that trigger the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway and subsequent interferon-β (IFN-β) production. UreC-mediated activation of the IFN-β pathway upregulates the expression of SR-A1 to form lipid droplets that facilitate Mtb replication. UreC inhibition via a urease inhibitor impaired Mtb growth within macrophages and in vivo. Thus, our findings identify mechanisms by which Mtb triggers a cascade of cellular events that establish a nutrient-rich replicative niche.
Identification of a regulatory pathway governing TRAF1 via an arthritis-associated non-coding variant
Authors: Qiang Wang, Marta Martínez-Bonet, Taehyeung Kim, Jeffrey A. Sparks, Kazuyoshi Ishigaki, Xiaoting Chen, Marc Sudman, Vitor Aguiar, Sangwan Sim, Marcos Chiñas Hernandez, Darren J. Chiu, Alexandra Wactor, Brian Wauford, Miranda C. Marion, Maria Gutierrez-Arcelus, John Bowes, Stephen Eyre, Ellen Nordal, Sampath Prahalad, Marite Rygg, Vibeke Videm, Soumya Raychaudhuri, Matthew T. Weirauch, Carl D. Langefeld, Susan D. Thompson, Peter A. Nigrovic
Journal: Cell Genomics (2023)

was among the first loci shown to confer risk for inflammatory arthritis in the absence of an associated coding variant, but its genetic mechanism remains undefined. Using Immunochip data from 3,939 patients with juvenile idiopathic arthritis (JIA) and 14,412 control individuals, we identified 132 plausible common non-coding variants, reduced serially by single-nucleotide polymorphism sequencing (SNP-seq), electrophoretic mobility shift, and luciferase studies to the single variant rs7034653 in the third intron of
A gB nanoparticle vaccine elicits a protective neutralizing antibody response against EBV
Authors: Cong Sun, Yin-Feng Kang, Xin-Yan Fang, Yi-Na Liu, Guo-Long Bu, Ao-Jie Wang, Yan Li, Qian-Ying Zhu, Hua Zhang, Chu Xie, Xiang-Wei Kong, Yong-Jian Peng, Wen-Jie Lin, Ling Zhou, Xin-Chun Chen, Zheng-Zhou Lu, Hui-Qin Xu, Dong-Chun Hong, Xiao Zhang, Ling Zhong, Guo-Kai Feng, Yi-Xin Zeng, Miao Xu, Qian Zhong, Zheng Liu, Mu-Sheng Zeng
Journal: Cell Host & Microbe (2023)
Deep scRNA sequencing reveals a broadly applicable Regeneration Classifier and implicates antioxidant response in corticospinal axon regeneration
Authors: Hugo J. Kim, Junmi M. Saikia, Katlyn Marie A. Monte, Eunmi Ha, Daniel Romaus-Sanjurjo, Joshua J. Sanchez, Andrea X. Moore, Marc Hernaiz-Llorens, Carmine L. Chavez-Martinez, Chimuanya K. Agba, Haoyue Li, Joseph Zhang, Daniel T. Lusk, Kayla M. Cervantes, Binhai Zheng
Journal: Neuron (2023)

Despite substantial progress in understanding the biology of axon regeneration in the CNS, our ability to promote regeneration of the clinically important corticospinal tract (CST) after spinal cord injury remains limited. To understand regenerative heterogeneity, we conducted patch-based single-cell RNA sequencing on rare regenerating CST neurons at high depth following PTEN and SOCS3 deletion. Supervised classification with Garnett gave rise to a Regeneration Classifier, which can be broadly applied to predict the regenerative potential of diverse neuronal types across developmental stages or after injury. Network analyses highlighted the importance of antioxidant response and mitochondrial biogenesis. Conditional gene deletion validated a role for NFE2L2 (or NRF2), a master regulator of antioxidant response, in CST regeneration. Our data demonstrate a universal transcriptomic signature underlying the regenerative potential of vastly different neuronal populations and illustrate that deep sequencing of only hundreds of phenotypically identified neurons has the power to advance regenerative biology.
Polyamine metabolism controls B-to-Z DNA transition to orchestrate DNA sensor cGAS activity
Authors: Chunyuan Zhao, Yunjin Ma, Minghui Zhang, Xiaoyan Gao, Wenbo Liang, Ying Qin, Yue Fu, Mutian Jia, Hui Song, Chengjiang Gao, Wei Zhao
Journal: Immunity (2023)
In vivo photopharmacology with light-activated opioid drugs
Authors: Shannan P. McClain, Xiang Ma, Desiree A. Johnson, Caroline A. Johnson, Aryanna E. Layden, Jean C. Yung, Susan T. Lubejko, Giulia Livrizzi, X. Jenny He, Jingjing Zhou, Janie Chang-Weinberg, Emilya Ventriglia, Arianna Rizzo, Marjorie Levinstein, Juan L. Gomez, Jordi Bonaventura, Michael Michaelides, Matthew R. Banghart
Journal: Neuron (2023)

Traditional methods for site-specific drug delivery in the brain are slow, invasive, and difficult to interface with recordings of neural activity. Here, we demonstrate the feasibility and experimental advantages of in vivo photopharmacology using "caged" opioid drugs that are activated in the brain with light after systemic administration in an inactive form. To enable bidirectional manipulations of endogenous opioid receptors in vivo, we developed photoactivatable oxymorphone (PhOX) and photoactivatable naloxone (PhNX), photoactivatable variants of the mu opioid receptor agonist oxymorphone and the antagonist naloxone. Photoactivation of PhOX in multiple brain areas produced local changes in receptor occupancy, brain metabolic activity, neuronal calcium activity, neurochemical signaling, and multiple pain- and reward-related behaviors. Combining PhOX photoactivation with optical recording of extracellular dopamine revealed adaptations in the opioid sensitivity of mesolimbic dopamine circuitry in response to chronic morphine administration. This work establishes a general experimental framework for using in vivo photopharmacology to study the neural basis of drug action.
Cognitive behavioral therapies for depression and anxiety in people with chronic disease: A systematic review and meta-analysis
Authors: Amelia J. Scott, Madelyne A. Bisby, Andreea I. Heriseanu, Yalda Salameh, Eyal Karin, Rhiannon Fogliati, Joanne Dudeney, Milena Gandy, Lauren F. McLellan, Bethany Wootton, Sarah McDonald, Ashleigh Correa, Nick Titov, Blake F. Dear
Journal: Clinical Psychology Review (2023)
Safety and efficacy of the new, oral, small-molecule, GLP-1 receptor agonists orforglipron and danuglipron for the treatment of type 2 diabetes and obesity: systematic review and meta-analysis of randomized controlled trials
Authors: Paschalis Karakasis, Dimitrios Patoulias, Konstantinos Pamporis, Panagiotis Stachteas, Konstantinos I. Bougioukas, Aleksandra Klisic, Nikolaos Fragakis, Manfredi Rizzo
Journal: Metabolism (2023)
Broadly potent anti-SARS-CoV-2 antibody shares 93% of epitope with ACE2 and provides full protection in monkeys
Authors: Craig Fenwick, Priscilla Turelli, Yoan Duhoo, Kelvin Lau, Cécile Herate, Romain Marlin, Myriam Lamrayah, Jérémy Campos, Line Esteves-Leuenberger, Alex Farina, Charlène Raclot, Vanessa Genet, Flurin Fiscalini, Julien Cesborn, Laurent Perez, Nathalie Dereuddre-Bosquet, Vanessa Contreras, Kyllian Lheureux, Francis Relouzat, Rana Abdelnabi, Pieter Leyssen, Yves Lévy, Florence Pojer, Roger Le Grand, Didier Trono, Giuseppe Pantaleo
Journal: Journal of Infection (2023)

Due to the rapid evolution of SARS-CoV-2 to variants with reduced sensitivity to vaccine-induced humoral immunity and the near complete loss of protective efficacy of licensed therapeutic monoclonal antibodies, we isolated a potent, broad-spectrum neutralizing antibody that could potentially provide prophylactic protection to immunocompromised patient populations.
From shape-shifting embryonic cells to oncology: The fascinating history of epithelial mesenchymal transition
Authors: Rosemary J. Akhurst
Journal: Seminars in Cancer Biology (2023)

Epithelial-to-mesenchymal transition or transformation (EMT) is a cell shape-changing process that is utilized repeatedly throughout embryogenesis and is critical to the attainment of a precise body plan. In the adult, EMT is observed under both normal and pathological conditions, such as during normal wounding healing, during development of certain fibrotic states and vascular anomalies, as well as in some cancers when malignant cells progress to become more aggressive, invasive, and metastatic. Epithelia derived from any of the three embryonic germ layers can undergo EMT, including those derived from mesoderm, such as endothelial cells (sometimes termed Endo-MT) and those derived from endoderm such as fetal liver stroma. At the cellular level, EMT is defined as the transformation of epithelial cells towards a mesenchymal phenotype and is marked by attenuation of expression of epithelial markers and de novo expression of mesenchymal markers. This process is induced by extracellular factors and can be reversible, resulting in mesenchymal-to-epithelial transformation (MET). It is now clear that a cell can simultaneously express properties of both epithelia and mesenchyme, and that such transitional cell-types drive tumor cell heterogeneity, an important aspect of cancer progression, development of a stem-like cell state, and drug resistance. Here we review some of the earliest studies demonstrating the existence of EMT during embryogenesis and discuss the discovery of the extracellular factors and intracellular signaling pathways that contribute to this process, with components of the TGFβ signaling superfamily playing a prominent role. We mention early controversies surrounding in vivo EMT during embryonic development and in adult diseased states, and the maturation of the field to a stage wherein targeting EMT to control disease states is an aspirational goal.